Epstein-Barr virus Rta downregulates a histone methyltransferase during viral reactivation
| Autor: | Chi-TingHsieh, 謝其庭 |
|---|---|
| Rok vydání: | 2015 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 103 Epstein-Barr virus (EBV) establishes life-long latent infection in more than 90% of human population without symptom, while viral reactivation into the lytic cycle is associated with some diseases including cancers. Previous studies revealed that cellular histone methyltransferases (HMTs) maintain EBV latency in B cells through epigenetic repression of viral lytic gene expression. Nevertheless, upon EBV reactivation, how the virus counteracts the epigenetic repression state remains unclear. In this study we found that the viral lytic infection was associated with reduction of several histone methyltransferases, and that suppressor of variegation 3-9 homolog 1 (SUV39H1), a methyltransferase of histone H3 lysine 9, was downregulated by ectopic expression of a viral lytic transactivator Rta. The Rta-mediated SUV39H1 downregulation was impeded by treatment with a proteosome inhibitor MG132, indicating that the underlying mechanism involves proteasomal degradation. Meanwhile, Rta-induced viral lytic gene expression was significantly reduced when SUV39H1 was overexpressed or recovered by MG132 treatment, suggesting that downregulation of SUV39H1 is important for efficient Rta-driven EBV reactivation. To further investigate the effects of Rta on epigenetic regulation, we generated recombinant Rta-knockout EBV by using a modified clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system, and have developed a strategy to isolate the recombinant viral clones with expected gene modification. This study will identify a novel active role of EBV in epigenetic control during viral reactivation, shedding light on the therapeutic potential of epigenetic intervention for EBV-associated diseases. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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